PK-PD based optimal dose and time for orally administered supra-pharmacological dose of melatonin to prevent radiation induced mortality in mice

Aims: The study reports preclinical pharmacokinetics (PK) and correlation with pharmacological effect at suprapharmacological dose of orally administered melatonin along with time and dose optimization, which have been lacking in earlier reports of radioprotection using melatonin. Methods: PK of melatonin in C57BL/6 mice was evaluated after dose of 250 mg/kg using HPLC. Tissue distribution study was conducted in vital organs following oral administration. Plasma total antioxidant capacity (TAC) was determined by ABTS(+) radical assay and was correlated to plasma concentrations of melatonin. Using the outcomes of PK and Pharmacodynamics (PD), survival study was conducted for optimization of 'drug radiation gap period' (DRGP). Optimal oral dose for radioprotection was determined using survival as an end point. Key findings: PK analysis of melatonin revealed T-max at 5 min with closely spaced another distinct concentration peak at 20 min. Plasma TAC of melatonin showed similar peaks at 5 min and 45 min, with the highest TAC at 45 min. Survival following a lethal (9 Gy) radiation dose was 20% and 40% after 5 and 45 min of melatonin administration, respectively. DRGP for melatonin was thus 45 min, while optimal oral dose ranged from 125 to 250 mg/kg. PK parameters at 250 mg/kg dose were qualitatively similar to low dose of melatonin, thus preventing chances of unexpected toxicity. Significance: Survival enhancement at 45 min suggested as probable interval required as 'DRGP'. The optimum oral therapeutic window appears large with no substantial toxicity. The outcomes will be useful in development of radioprotectors as well as other therapeutic applications.